**4. Treatment**

#### **4.1. Preventive treatment**

Preventive treatment is defined as a systematic treatment that can avoid or reduce the incidence of PTLDs; it only concerns EBV-positive PTLDs. In this area, no study specifically targets heart-transplant patients. The interest of antivirals, especially ganciclovir, does not seem to be confirmed. On the other hand, polyvalent CMV immunoglobulins (in fact rich in anti-EBV immunoglobulins) have shown, in a retrospective study, an interest in kidney-transplant patients, suppressing the risk of PTLD occurring during the year of prevention in more than 2000 patients [7], whereas no preventive effect was detected in patients receiving ganciclovir. However, a prospective study, admittedly of a smaller size, did not show any difference between a preventive treatment with ganciclovir + placebo versus ganciclovir + immunoglobulins against CMV [8]. Currently, no preventive treatment is recommended in cardiac-transplant patients.

#### **4.2. Preemptive treatment**

Preemptive treatment only concerns EBV-positive PTLDs; it consists of treating patients according to their EBV viral load. It is based on the fact that the majority of EBV-positive PTLDs are preceded by an increase in EBV load or a simple positivity in the case of primary infections [8]. The most classic attitude is to reduce immunosuppression, where possible [9–11]. As the EBV reservoir is the B lymphocyte, rituximab has also been used successfully in this setting, especially after allografts of hematopoietic stem cells [12]. Much less available and usable only in the context of protocols, anti EBV T lymphocytes, either autologous (taken from the patient and stimulated ex vivo) [13, 14], or allogeneic (from healthy donor lymphocyte banks) [15], have been used effectively in case of EBV reactivation. Specifically developed in cardiac-transplant patients, a treatment algorithm has been validated on nearly 300 patients whose immunosuppression was identical [16]; it is based initially on the serological status before transplant and then on the EVL carried out at each follow-up visit, for at least 1 year. The algorithm is described in **Figure 3**. In summary, immunosuppression is reduced as soon as the EVL is positive if the recipient was seronegative, since it is then a primary EBV infection, that is, when the EVL is greater than 105 copies/ml in other case.

Paraclinically, the EBV viral load (EVL) is essential, and a high rate is in favor of an EBV-positive PTLD; it is also a good marker of response during treatment. Imaging, CT scanning, or especially PET-CT scan are diagnostic [6] and allow an adequate extension assessment. The appearance of tumors and nodes is similar to that of lymphomas of immunocompetent patients. In the particular case of cerebral PTLD, the lesions are necrotic, in the form of a cockade, identical to toxoplasmic lesions, as in patients with HIV (**Figure 2**). MRI spectrometry can point to PTLD rather than infection. In the absence of contraindication, a lumbar puncture is necessary; it must include a cytology with anti-CD20 labeling on a slide, a phenotyping, a search for B clonality, and an EBV viral load. If lumbar puncture is found in lymphoma cells, cerebral biopsy is not necessary.

Preventive treatment is defined as a systematic treatment that can avoid or reduce the incidence of PTLDs; it only concerns EBV-positive PTLDs. In this area, no study specifically targets heart-transplant patients. The interest of antivirals, especially ganciclovir, does not seem to be confirmed. On the other hand, polyvalent CMV immunoglobulins (in fact rich in anti-EBV immunoglobulins) have shown, in a retrospective study, an interest in kidney-transplant patients, suppressing the risk of PTLD occurring during the year of prevention in more than 2000 patients [7], whereas no preventive effect was detected in patients receiving ganciclovir. However, a prospective study, admittedly of a smaller size, did not show any difference between a preventive treatment with ganciclovir + placebo versus ganciclovir + immunoglobulins against CMV [8]. Currently, no preventive treatment is recommended in cardiac-transplant patients.

Preemptive treatment only concerns EBV-positive PTLDs; it consists of treating patients according to their EBV viral load. It is based on the fact that the majority of EBV-positive

**4. Treatment**

186 Heart Transplantation

**4.1. Preventive treatment**

**Figure 2.** Cerebral PTLD, MRI in T1 with gadolinium.

**4.2. Preemptive treatment**

**Figure 3.** Algorithm for preemptive treatment of PTLD after heart transplantation, depending on serological status and EBV viral load.

An injection of 375 mg/m<sup>2</sup> of rituximab is performed, in addition to the decrease in immunosuppression, if the EVL is greater than 106 copies/ml, or if the initial decrease in immunosuppression fails. No cases of EBV-positive PTLD were diagnosed in this series, which is statistically significant in historical comparison with more than 800 patients transplanted in the same unit before using this algorithm.

### **4.3. PTLD treatment**

## *4.3.1. Decrease of the immunosuppression*

The decrease in immunosuppression remains the benchmark for the initial management of PTLDs. It allows complete response in less than 10% of cases, mainly in early forms [17, 18]. As the median time of response is 3.6 months [19], it is conventional to wait 4 weeks before evaluating the response to the decrease of immunosuppression, except in case of progression. Even in the event of failure, it is necessary to keep the immunosuppression as low as possible because it seems to potentiate immunochemotherapy [20].

#### *4.3.2. Immunochemotherapy*

In the case of failure of the reduction of immunosuppression, in CD20-positive PTLDs, which represents the vast majority of cases, sequential immunochemotherapy is the reference treatment, validated by two European prospective studies [3, 21]. The processing algorithm is shown in **Figure 4**. The first phase is to use only rituximab monotherapy and wait 3 weeks before evaluating the response, in case of complete remission, which is found in one-third of cases; rituximab is continued alone, this to avoid chemotherapy, in other cases, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is used, a reference chemotherapy of NHL, but only for four cures against six to eight in the immunocompetent patients, and a case is presented in **Figure 5**. This therapeutic attitude gives 88% of response, 70% of complete response, and a median survival of 6.6 years, which currently constitutes the best results of the literature for a prospective study. In pediatric patients, lightened chemotherapy regimens have been proposed, without doxorubicin or vincristine, making it possible to obtain an overall survival of 83% at 2 years and an event-free survival of 71% [22].

## **4.4. Specific PTLDs**

#### *4.4.1. PTLD of the central nervous system*

PTLDs in the central nervous system account for 10% of PTLDs, and even if they occur mostly after kidney transplants, they are not uncommon after cardiac transplantation. Their management is not consensual but should include if possible a reduction of immunosuppression and methotrexate adapted to the renal function, and the addition of aracytine and rituximab is recommended. In case of failure or contraindication, radiotherapy is an option. In a recent retrospective study, the response rate was 60% but the 3-year survival was only 43% [4].

*4.4.2. Classical Hodgkin PTLD*

**Figure 4.** Algorithm to treat CD20-positive PTLD in first line.

Hodgkin PTLD should be treated as Hodgkin's immunocompetent patients, without ritux-

Post-Heart Transplantation Lymphoproliferations http://dx.doi.org/10.5772/intechopen.76042 189

imab (Hodgkin's are CD20 negative); their prognosis is excellent.

#### Post-Heart Transplantation Lymphoproliferations http://dx.doi.org/10.5772/intechopen.76042 189

**Figure 4.** Algorithm to treat CD20-positive PTLD in first line.

#### *4.4.2. Classical Hodgkin PTLD*

An injection of 375 mg/m<sup>2</sup>

188 Heart Transplantation

**4.3. PTLD treatment**

*4.3.2. Immunochemotherapy*

of 71% [22].

**4.4. Specific PTLDs**

was only 43% [4].

*4.4.1. PTLD of the central nervous system*

nosuppression, if the EVL is greater than 106

the same unit before using this algorithm.

*4.3.1. Decrease of the immunosuppression*

because it seems to potentiate immunochemotherapy [20].

of rituximab is performed, in addition to the decrease in immu-

nosuppression fails. No cases of EBV-positive PTLD were diagnosed in this series, which is statistically significant in historical comparison with more than 800 patients transplanted in

The decrease in immunosuppression remains the benchmark for the initial management of PTLDs. It allows complete response in less than 10% of cases, mainly in early forms [17, 18]. As the median time of response is 3.6 months [19], it is conventional to wait 4 weeks before evaluating the response to the decrease of immunosuppression, except in case of progression. Even in the event of failure, it is necessary to keep the immunosuppression as low as possible

In the case of failure of the reduction of immunosuppression, in CD20-positive PTLDs, which represents the vast majority of cases, sequential immunochemotherapy is the reference treatment, validated by two European prospective studies [3, 21]. The processing algorithm is shown in **Figure 4**. The first phase is to use only rituximab monotherapy and wait 3 weeks before evaluating the response, in case of complete remission, which is found in one-third of cases; rituximab is continued alone, this to avoid chemotherapy, in other cases, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is used, a reference chemotherapy of NHL, but only for four cures against six to eight in the immunocompetent patients, and a case is presented in **Figure 5**. This therapeutic attitude gives 88% of response, 70% of complete response, and a median survival of 6.6 years, which currently constitutes the best results of the literature for a prospective study. In pediatric patients, lightened chemotherapy regimens have been proposed, without doxorubicin or vincristine, making it possible to obtain an overall survival of 83% at 2 years and an event-free survival

PTLDs in the central nervous system account for 10% of PTLDs, and even if they occur mostly after kidney transplants, they are not uncommon after cardiac transplantation. Their management is not consensual but should include if possible a reduction of immunosuppression and methotrexate adapted to the renal function, and the addition of aracytine and rituximab is recommended. In case of failure or contraindication, radiotherapy is an option. In a recent retrospective study, the response rate was 60% but the 3-year survival

copies/ml, or if the initial decrease in immu-

Hodgkin PTLD should be treated as Hodgkin's immunocompetent patients, without rituximab (Hodgkin's are CD20 negative); their prognosis is excellent.

complete remissions were obtained from 33 treated patients, but many of these patients had not received rituximab in the first line [23]. The ATARA Biotherapeutics laboratory begins in 2018, a phase 3 study using allogeneic anti-EBV lymphocytes against placebo in relapsed or refractory PTLDs, which could allow in the medium term to offer this therapy

Post-Heart Transplantation Lymphoproliferations http://dx.doi.org/10.5772/intechopen.76042 191

CAR-T cells, which are being developed in lymphoid hemopathies of immunocompetent patients, have not yet been used in an immunocompromised context that could potentially

Anti-PD1/PDL1 antibodies by improving immunity expose patients to rejection of the transplanted organ, sometimes abruptly; their indication in PTLDs, mainly of Hodgkin type, is

PTLDs are a clearly defined entity, representing the most increased cancer among cardiactransplant recipients compared to the general population. Its management, from preemptive treatment to curative treatment, has been considerably improved in order to obtain a survival rate similar to that of other transplant recipients. The treatment deviates significantly from that of immunocompetent lymphomas and requires management by teams accustomed to this type of pathology, both for the follow-up of the transplant and for the hematological

treatment. The development of cell therapies is very likely the next step in progress.

Service d'Hématologie Clinique, Hôpital de la Pitié-Salpêtrière, Paris, France

[1] Opelz G, Döhler B. Lymphomas after solid organ transplantation: A collaborative trans-

[2] Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. Journal of the American Medical Association.

plant study report. American Journal of Transplantation. 2004;**4**(2):222-230

Address all correspondence to: sylvain.choquet@aphp.fr

strongly discouraged and should only be proposed by the last resort [24].

to all centers treating PTLDs.

reduce their effectiveness.

**5. Conclusion**

**Author details**

Sylvain Choquet

**References**

2011;**306**(17):1891-1901

**4.6. CAR-T cells and anti-PD1/anti-PDL1**

**Figure 5.** Response of a monomorphic diffuse large B cell PTLD after four rituximab and after four R-CHOP.

### *4.4.3. Plasmacytic hyperplasia PTLD*

This rare form of early lesions can be treated with radiotherapy or lymphoma chemotherapy.

#### *4.4.4. T-cell lymphoma PTLD*

This type of PTLD has a very poor prognosis, rituximab is useless and the classic chemotherapy-type CHOP has little effectiveness. In case of localized form, radiotherapy may be useful.

#### *4.4.5. Relapses*

Relapses after complete remission are rare; if they occur late after the first PTLD, a comparison of the clones is necessary because a second PTLD, independent of the first one, is possible; if it is the case, the algorithm of first line, describes previously, can be reused, and the maximum dose of anthracycline will not be reached. In other cases, NHL treatments of immunocompetent patients in relapse may be used, even hematopoietic stem cell autograft.

#### **4.5. Cell therapy**

Cell therapy is not yet available outside study protocols. Its principle is to use T cells specifically directed against EBV antigens, so it is only applicable to half of PTLDs. It is mostly the allogeneic lymphocyte banks, from healthy donors, that are promising. The lymphocytes are selected according to the HLA typing of the tumor. In the Scottish experience, 12 complete remissions were obtained from 33 treated patients, but many of these patients had not received rituximab in the first line [23]. The ATARA Biotherapeutics laboratory begins in 2018, a phase 3 study using allogeneic anti-EBV lymphocytes against placebo in relapsed or refractory PTLDs, which could allow in the medium term to offer this therapy to all centers treating PTLDs.
