Hematology: priorities according to Prof. Ewa Lech-Marańda

What are the therapeutic priorities in hematology for the current year?

In the last 5 years, a great deal has been done in the reimbursement area in hematology - 75 new molecules have been reimbursed in 26 hematological diagnoses, both cancerous and non-cancerous. It can be said that we have entered a new era in terms of access to modern therapies, and we are providing treatment according to European standards. However, as worldwide progress in the field of hematology is very great and treatment standards are changing literally before our eyes, new needs for access to modern therapies are constantly arising.

Among the most important reimbursement needs for this year, I would place access to CAR-T therapy for patients aged 26 and over with relapsed or refractory B-cell acute lymphoblastic leukemia at the top of the list. Currently, CAR-T therapy is reimbursed under the B.65 drug program for patients with this diagnosis, but only for children and young adults up to the age of 25 - this, by the way, was the first registration indication for CAR-T therapy in B-cell precursor acute lymphoblastic leukemia. Under the same drug program, in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, we can use monoclonal antibodies, i.e. blinatumomab (bispecific antibody) or ozogamycin inoztuzumab (conjugated antibody), but there are clinical situations in which relapse occurs after treatment with antibodies, and then CAR-T therapy is the only option for these patients.

Second among reimbursement needs, I would point to access to modern bispecific antibodies for patients with B-cell lymphomas, both aggressive and indolent (so-called "slow") for refractory or relapsed disease. For patients with aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL), the European Medicines Agency (EMA) has registered two bispecific antibodies, namely epcortamab and glofitamab. These are antibodies directed against the CD20 antigen located on lymphoma cells and the CD3 antigen located on cytotoxic T lymphocytes. epcortamab and glofitamab are registered for patients who have received at least 2 prior lines of treatment. On the other hand, for patients with follicular lymphoma (indolent lymphoma), the EMA last year registered a bispecific antibody called mosunetuzumab. It is also an anti-CD20 and anti-CD3 antibody, which is indicated in patients after 2 prior lines of treatment.

Another need is for a bispecific antibody, teclistamab, for plasmocytic myeloma patients, which targets the B-cell maturation antigen (BCMA) present on plasma cells and the CD3 antigen on cytotoxic T lymphocytes. Among the therapies for plasmocytic myeloma patients, it is also important to mention the need to expand access to drugs already reimbursed, but now necessary in other, more modern and effective combinations, such as a therapy regimen with daratumumab, carfilzomib and dexamethasone, or a regimen with isatuximab, carfilzomib and dexamethasone. Both isatuximab and daratumumab are reimbursed for patients with refractory or relapsed plasmocytic myeloma, but in combinations with other drugs.

As a fourth reimbursement need, I would identify CAR-T therapy for patients with diffuse large B-cell lymphoma (DLBCL) when the disease is found to be refractory to 1st-line therapy or has relapsed rapidly, i.e. within 12 months of completing 1st-line treatment. CAR-T therapy is currently available for patients with aggressive B-cell lymphoma under the B.12.FM drug program after prior at least 2 lines of treatment. According to global recommendations and EMA registration, CAR-T therapy is now recommended at an earlier stage of treatment, i.e. after failure of 1st line treatment.

I also see an urgent need for reimbursement for patients with non-cancerous hematological diseases, specifically in the ultra-rare disease immune thrombotic thrombocytopenic purpura, in which the use of caplacizumab, i.e. a monoclonal antibody that blocks the attachment of platelets to the large multimeters of von Willebrand factor, in parallel with total plasma exchange procedures, allows for effective inhibition of thromboembolic complications in this life-threatening disease.

In lymphoma patients, are bispecific antibodies an effective therapy when there is virtually nothing left for the patient?

This is what we can say, because according to the registration indications, bispecific antibodies should already be used after the previous 2 treatment failures, secondly, these drugs are also effective in patients with relapse after CAR-T therapy, or not responding to this therapy. If CAR-T therapy is used according to the current drug program in the third line, then bispecific antibody can be used in the fourth line of treatment if there is a relapse after CAR-T. It is worth remembering that bispecific antibodies can also be used in patients who are ineligible for CAR-T therapy either because of very rapidly progressing disease or because of comorbidities contraindicating CAR-T therapy.

It is worth mentioning that CAR-T therapy is available at major university centers in Poland.

Yes, and the same is true in most European countries, where CAR-T therapy can be used only in those centers that have passed the certification process and that have hematopoietic stem cell transplantation centers in their structure, so in practice these are large university centers or institutes. The waiting time for the preparation of modified CAR cells is not insignificant. This is a complicated technological process, which takes about 4 weeks, i.e. first the patient's own lymphocytes must be collected, which after appropriate preparation are sent to a laboratory in Europe, then they are subjected to genetic modification, i.e. a gene encoding the so-called chimeric receptor (CAR) , which is able to recognize and destroy the lymphoma cell, is introduced into the T lymphocytes, then the modified lymphocytes are multiplied, frozen and sent to a center in Poland, where the patient is. Of course, not every patient, due to the dynamics of his disease, can wait for CAR-T cells to be prepared. In contrast, the advantage of bispecific antibodies, which have a similar registration to the first indication for CAR-T therapy, is that they are available immediately, i.e. off-the- shelf, if only they were reimbursed. Bispecific antibodies, depending on their type, can be used for a limited period of time or until disease progression, while CAR-T therapy is a once-daily administration of the drug. Thus, both treatment methods, i.e. CAR-T therapy and bispecific antibodies, have their strong and weaker aspects.

When will patients be able to enjoy the benefits of the National Hematology Network?

In order to properly implement the National Hematology Network (NHN), it is necessary to conduct a pilot beforehand. The draft of the KSH pilot was submitted for public consultation last August, has been revised in accordance with the comments submitted, and is currently awaiting further processing at the Ministry of Health. The KSH pilot is based on three main elements: reference of hematology centers and their mutual cooperation, providing coordinated and comprehensive care for hematology patients based on patient pathways in all centers included in the pilot, and monitoring the quality of the diagnostic and therapeutic process and the quality of operation of the new organizational model. As part of the pilot, we plan to prepare standards of management based on specific diagnostic and therapeutic pathways for patients with seven blood cancers. Coordination of care for a blood cancer patient should be understood as horizontal and vertical coordination. Horizontal coordination will take place within a given center, where there will be a dedicated coordinator for the patient, whose role will be to guide the patient through the various stages of treatment, including helping to arrange specialized tests and consultations. Vertical coordination, i.e. between hematology centers, is intended to coordinate the patient's pathway in the event that certain procedures or stages of treatment need to be performed at another hematology center. Comprehensiveness of treatment in hematology should be understood not only as the provision of comprehensive therapy at the various stages of cancer treatment, but also as the provision of multidisease consultations for the patient with multimorbidity, which applies to most hematology patients, such as cardiology, pulmonology, nephrology, but also the care of a clinical psychologist, clinical nutritionist, or rehabilitation specialist. It should be possible to provide such consultations in both inpatient and outpatient modes. In the pilot, we made certain assumptions about the functioning of hematological care, but whether the adopted model will prove optimal will only be shown by the results of the pilot. The goal of the pilot of the National Hematology Network is to improve access to diagnostics and hematooncological treatment, but also to ensure the quality of the diagnostic and treatment procedures performed, so as to improve the prognosis and prolong the survival of patients with blood cancers. We also want to include some elements of cooperation between hematology centers and primary care physicians in the KSH pilot. We would like to develop guidelines for PCPs on basic diagnosis of blood cancers, including defining the indications for referring a patient to an outpatient clinic or hematology department. We would also like to prepare a standard of chronic care for patients with blood cancers, so that the PCP would receive information on the principles of managing a hematological patient, such as which antibiotics are best to use during infection, whether and when to vaccinate patients, etc. Of course, in addition to preparing guidelines, we would also like to be able to organize training in this area.