Hematology

It is a disease that can also be seen in young people, but because the incidence increases with age, the median age of patients who visit our hospital is about 60 years old. The goal of treatment is to cure the disease in younger patients and to cure or give time to a normal life at home in the elderly. To that end, treatment with anticancer drugs (chemotherapy) is first performed with the aim of restoring blood components to normal (called complete remission).

Even after complete remission, treatment can be continued with the aim of curing, but for patients who need only several chemotherapy sessions, and for patients who need allogeneic hematopoietic stem cell transplantation in addition to chemotherapy. split up. Allogeneic hematopoietic stem cell transplantation has a high probability of long-term survival, but complications of the treatment itself can be life-threatening. It is important to determine the need for allogeneic hematopoietic stem cell transplantation early after starting treatment.

At our hospital, we examine mutated genes that affect the prognosis of leukemia and the amount of residual leukemia cells over time using multiplex flow cytometry and high-sensitivity genetic analysis, and determine the indication for allogeneic hematopoietic stem cell transplantation. I'm here. In addition, at our hospital, physiotherapists provide cancer rehabilitation to patients who are in a clean room during leukemia treatment. are doing

These efforts have improved treatment outcomes for patients who do not have genetic abnormalities with poor prognosis.

It is a disease that is common in children, and there are many patients under the age of 40 in the field of internal medicine. For patients under the age of 25, chemotherapy, which has been performed in Pediatrics, is performed, and for patients over that age, HyperCVAD/HD-MA, a treatment method devised in the field of internal medicine, is mainly performed.

It is a disease that is common in children, and there are many patients under the age of 40 in the field of internal medicine. For patients under the age of 25, chemotherapy, which has been performed in Pediatrics, is performed, and for patients over that age, HyperCVAD/HD-MA, a treatment method devised in the field of internal medicine, is mainly performed.

In the field of internal medicine, there are many Philadelphia chromosome (Ph)-positive patients (about 40%), and such patients are treated with tyrosine kinase inhibitors. In the case of chemotherapy alone, maintenance therapy is performed for 2 years, but in Ph-positive patients, allogeneic hematopoietic stem cell transplantation is aggressively performed. In addition, even for other patients, we determine the indication for allogeneic transplantation by examining the minimal amount of residual tumor using genetic analysis. Reducing the residual tumor burden as much as possible with chemotherapy is of utmost importance in both chemotherapy and allogeneic transplantation.

The introduction of new drugs such as rituximab and bendamustine in the 21st century has resulted in significant improvements in treatment outcomes in B-cell lymphoma. It is expected that many new drugs will be introduced in the future. The five-year survival rate for diffuse large B-cell lymphoma, the most common form, is 68%.

The introduction of new drugs such as rituximab and bendamustine in the 21st century has resulted in significant improvements in treatment outcomes in B-cell lymphoma. It is expected that many new drugs will be introduced in the future. The five-year survival rate for diffuse large B-cell lymphoma, the most common form, is 68%.

In low-grade B-cell lymphoma, which progresses slowly, the policy of living longer while coexisting with the disease has become a realistic option, rather than seeking a cure for the disease.

On the other hand, in peripheral T-cell lymphoma and adult T-cell leukemia, the results of chemotherapy alone are not sufficient, and autologous or allogeneic hematopoietic stem cell transplantation is also considered. In any case, in the treatment of malignant lymphoma, pathological classification based on new ideas and cytogenetic testing to complement it are indispensable. In our department, when treating all malignant lymphoma patients, we determine short-term and medium- to long-term treatment policies based on pathological and cytogenetic examination results.

This disease is accompanied by organ symptoms other than blood, such as brittle bones and fractures, and the need for hemodialysis due to renal dysfunction. It used to be a difficult disease to treat, but new drugs that have appeared in the 21st century are making remarkable improvements in treatment outcomes.

There are six types of drugs used. namely, steroids, alkylating agents (melphalan, cyclophosphamide, etc.), proteosome inhibitors (bortezomib, carfelzomib, ixazomib), immunomodulators called IMiDs (thalidomide, lenalidomide, pomalidomide), antibody preparations (elotuzumab, daratumumab). ), and others (panopinostat, doxorubicin, etc.). It is common to use a combination of 2-3 of these 6 drugs, but all drugs other than steroids, alkylating agents, and doxorubicin were launched after 2006, especially from 2015 to 2017. Six drugs have been released over the years. We are currently testing all over the world to find out what kind of combination is good and in what order it should be used. In fact, there are many drug combinations that have not been confirmed to interact with each other, so the actual treatment method is selected from about 10 combinations of drugs whose safety has been confirmed.

The goal of treatment is long-term asymptomatic survival. I hope that it will lead to healing as an extension of that. For long-term survival without subjective symptoms, it is considered desirable to reduce the tumor burden of myeloma to the extent that immunofixation and free light chain methods are negative or normalize. Specifically, the initial treatment should be a three-drug combination therapy, followed by autologous hematopoietic stem cell transplantation with high-dose chemotherapy for patients aged 70 years or younger, followed by annual maintenance therapy. is common, but we aim to select the best treatment according to the patient's medical condition. We are also participating in many clinical trials of new drugs that have not been released in Japan, so please feel free to contact us.

Depending on the probability of developing leukemia, it is roughly divided into a low-risk group and a high-risk group. For low-risk myelodysplastic syndromes, in addition to supportive care such as blood transfusions, erythropoietin therapy, immunosuppressive therapy, and depending on the disease type, lenalidomide are used to restore hematopoiesis.

In high-risk group myelodysplastic syndrome, chemotherapy and azacitidine treatment according to acute myelogenous leukemia are performed for the purpose of preventing the transition to leukemia. Both low-risk and high-risk groups require allogeneic hematopoietic stem cell transplantation to cure the disease. Especially in high-risk groups, allogeneic hematopoietic stem cell transplantation is actively performed.

Allogeneic hematopoietic stem cell transplantation constitutes two wheels of a cart together with chemotherapy in the treatment of hematopoietic malignancies. However, due to the risk of serious adverse events, such as graft-versus-host disease, which can sometimes be fatal, we do not perform this procedure on patients over the age of 70. At our hospital, allogeneic hematopoietic stem cell transplantation can be performed without waiting time. For various complications after allogeneic hematopoietic stem cell transplantation, the comprehensive virus analysis of the Advanced Medical Center provides important information.

A hematopoietic stem cell donor is required to perform allogeneic hematopoietic stem cell transplantation. Potential donors include the patient's relatives such as siblings and children, unrelated donors from bone marrow banks, and stored cord blood from cord blood banks. It is important to protect the privacy of patients and donor candidates when searching for donors among the patient's relatives. At our hospital, a hematopoietic cell transplantation coordinator certified by the Japan Society for Hematopoietic Cell Transplantation plays this role. In addition, transplant patients may experience various complications even after discharge from the hospital, and may require precautions or restrictions in their daily lives.

Nurses who have received training from the Japan Society for Hematopoietic Cell Transplantation for the purpose of resolving questions about daily life after transplantation, enabling them to live more comfortable lives, and facilitating self-management of their physical conditions. We also have a long-term follow-up outpatient after transplantation by a doctor.

CAR-T therapy is an innovative treatment that uses the patient's own immune system to attack cancer by modifying T cells, a type of white blood cell, by gene transfer and administering them to patients. On November 26, 2020, our hospital was certified as a facility capable of providing CAR-T cell therapy (Kymriah®), a new therapeutic agent for leukemia and lymphoma.

CAR-T cell therapy is a treatment that uses T cells modified to attack cancer cells by introducing a "chimeric antigen receptor (CAR)". Kymriah® collects T cells from patients, creates CAR-T cells that target the CD19 protein of acute lymphoblastic leukemia, and returns them to the patient.

*This content is intended for doctor and is intended to deepen the understanding of this medical institution, and is not intended for publicity or advertising for the general public.

Nice to meet you. My name is Tadakazu Kondo, and I am Director Hematology Department Kobe City Medical Center General Hospital.

Our department has eight full-time doctor and six Senior Resident, and we treat patients with hematopoietic tumors (acute leukemia, malignant lymphoma, multiple myeloma, myeloproliferative tumors, myelodysplastic syndromes, etc.) and non-neoplastic blood diseases (aplastic anemia, idiopathic thrombocytopenic purpura, etc.). We see 250-300 new patients a year, and perform 50-60 hematopoietic stem cell transplants a year, including autologous and allogeneic transplants, making us one of the largest in the Kinki region in terms of both the number of patients and the number of transplants. We also receive many requests for clinical trials of new drugs, and we are actively working on these.

In recent years, many molecular targeted drugs have been used to treat hematopoietic tumors. In particular, CAR-T therapy, a groundbreaking treatment for malignant lymphoma and acute lymphoblastic leukemia, has been introduced and approved for insurance coverage in Japan since March 2019. CAR-T therapy is only approved in a limited number of facilities because a strict cell management system is required for the handling of apheresis products (such as sterile preparation) and the cryopreservation of cell preparations. Our hospital aims to introduce CAR-T therapy early, and as a result, we have built an operational system in cooperation with the pharmacy department, transfusion testing management office, cell and genetic testing office, and Clinical Engineering, and were certified as a facility in November 2020, quite early for a city hospital. We will actively accept cases that request CAR-T therapy from other hospitals at our hospital.

Chuichi Kondo
Director Hematology

Efforts of new treatment for lymphoid tumors in our department

Did you know that in recent years, breakthrough treatments have been developed for acute lymphocytic leukemia and malignant lymphoma?
Traditionally, these diseases have been treated with cytotoxic anticancer drugs and antibody preparations such as rituximab, and for some acute lymphoblastic leukemia, molecular targeted drugs such as imatinib have been used in combination. rice field. In difficult cases, high-dose chemotherapy combined with autologous peripheral blood stem cell transplantation and allogeneic hematopoietic stem cell transplantation have been performed.

The development of immune checkpoint inhibitors such as nivolumab has revealed that T lymphocytes can exert remarkable anti-tumor effects. Unfortunately, hematopoietic malignancies for which immune checkpoint inhibitors are effective are limited. However, a treatment method that uses the power of the patient's T lymphocytes to overcome blood cancer has been developed using a new technology called BiTE or CAR-T, which is comparable to conventional anticancer drugs and molecular targeted drugs. It has amazing therapeutic effects.

Currently, both BiTE and CAR-T are covered by insurance only for tumors that express the CD19 antigen, and BiTE is only applicable to B-cell progenitor acute lymphoblastic leukemia, and CAR-T is also a progenitor. Limited to B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. BiTE can be used at any medical facility that has Board Certified Member of the Japanese Society of Hematology, but CAR-T is available at limited facilities. As of January 2021, only 19 facilities nationwide, 6 facilities in the Kinki area, and 2 facilities including our hospital in Hyogo Prefecture have been announced.

Dr. Satoshi Yoshioka, M.D. of our department, will explain the details of CAR-T.

New cell therapy for relapsed or refractory B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma: CAR-T cell therapy

Nice to meet you Kobe City Medical Center General Hospital HematologyM.D. My name is Satoshi Yoshioka (Satoshi Yoshioka).
In this article, we introduce tisagenlecleucel (Kymriah, Novartis Pharma K.K.), a CAR-T cell therapy formulation targeting CD19, which was approved as the first CAR-T cell therapy in Japan and was difficult to cure with conventional treatment, as a new treatment for patients with refractory B-ALL and DLBCL, which was difficult to cure with conventional treatment.
At that time, the treatment cost of 33.49 million yen per treatment was a hot topic in the world, and many people may have heard of the name, but we hope that it will be an opportunity for you to know the significance of Kymriah treatment.

• "Kymriah" is a registered trademark of Novartis Pharma K.K.

Hematology M.D.
Satoshi Yoshioka​
Specialized Fields
General hematology
Academic Society Specialist・ Certified Physician
The Japanese Society of Internal Medicine Certified Physician Board Certified Fellow of the Japanese Society of Internal Medicine (FJSIM) ・Supervising Doctor
The Japanese Society of Hematology Certified Board Certified Member of the Japanese Society of Hematology ・Supervising Doctor
Japanese Society for Hematopoietic Cell Transplantation Certified Physician etc.

Overview of Kymriah Treatment

Kymriah is a cell therapy formulation using CAR-T cells obtained by transfecting a chimeric antigen receptor (CAR) that targets the CD19 antigen expressed on the surface of B-cell tumors into previously collected patient T cells. .

CAR-T cells are activated when they interact with tumor cells, release cytotoxic proteins such as perforin and granzyme, and exert antitumor effects by inducing tumor cell death. Unlike allogeneic hematopoietic stem cell transplantation, which expects the antitumor effect of donor T cells against tumor cells, the use of autologous T cells reduces the risk of graft-versus-host disease (GVHD) and its treatment, such as seen in allogeneic transplantation. It is excellent in that adverse events such as infectiousness can be avoided.

Kymriah treatment begins with the harvesting of patient T cells (leukoapheresis). In other words, the fact that medical institutions are responsible for part of the process of manufacturing Kymriah is very different from conventional treatment.

Of course, formulations are required to meet certain standards of quality, so strict examinations must be cleared in order to be certified as an implementing medical institution, and the number of facilities that can provide this treatment is still limited nationwide. At our hospital, we have been able to implement it since December 2020 after receiving certification from the examination.

Diseases and Conditions Targeted by Kymriah

In Japan, relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) and relapsed or refractory CD19-positive diffuse large B-cell lymphoma (DLBCL) Effective and covered by insurance. Due to the high cost and limited number of medical institutions, Kymriah treatment for both diseases requires careful judgment of indications.

Common exclusion requirements for both diseases are as follows:

1. Patients not confirmed to beCD19 antigen positive
2. If you have central nervous system lesions
3. Patients with other malignant tumors
4. Patients previously treated with Kymriah (no retreatment allowed)

B-ALL has an age limit of 25 years or younger at the time of administration.

In addition, hepatitis B or C virus carriers and patients with a history of hepatitis should be carefully administered (patients with active infection and patients who are HBc antibody positive alone are not indicated), and HIV-infected patients are not indicated. Of course, patients with active infections and patients with severe organ dysfunction are also exempt.

Specific indications for each disease are detailed below. However, in reality, there are various medical conditions and pre-existing conditions of patients, so please feel free to consult us when it is judged that there is an indication.

1. Relapsed or refractory CD19 positive B-ALL

1) Patients for whom indications are considered
: Patients who meet any of the following conditions and are not eligible for autologous hematopoietic stem cell transplantation because hematopoietic stem cells cannot be collected, have complications, or have relapsed after autologous hematopoietic stem cell transplantation.

• Newly diagnosed refractory DLBCL: Patients who did not achieve a complete response or who achieved a complete response but relapsed after receiving 2 or more lines of chemotherapy.
• Relapsed/refractory DLBCL: Patients who received at least one line of salvage chemotherapy after recurrence and did not achieve a complete response or had a complete response but relapsed.
• Transformed DLBCL from Follicular Lymphoma: ≥2 lines of chemotherapy AND at least 1 line of chemotherapy after transformation with no or complete response Patients with relapse.

2) Inapplicable patients

• Patients with a history of allogeneic hematopoietic stem cell transplantation
• Chemotherapy-naïve patients including rituximab and anthracycline antineoplastic agents
• Patients with T-cell/histiocyte-rich large B-cell lymphoma (THRBCL), primary cutaneous DLBCL, primary mediastinal B-cell lymphoma (PMBCL), EBV-positive DLBCL (elderly), Richter's syndrome, and Burkitt's lymphoma

Treatment results of Kymriah

As mentioned above, Kymriah treatment is indicated for patients who are difficult to cure with conventional treatment. In fact, there have been cases in which patients who had no other means of treatment and had transitioned to palliative care received Kymriah and returned to work within six months of treatment.
Here, we will introduce specific treatment results based on the results of clinical trials and the latest paper reports.

1. Relapsed or refractory CD19 positive B-ALL

First, I would like to introduce the results of the global phase II study (ELIANA study) that served as the basis for insurance coverage.
Seventy-five relapsed/refractory B-ALL patients with a median age of 11 (3-23 years) were treated. The median follow-up period was 9.92 (0.4-22.8) months, and 61 patients (82%) achieved complete hematologic remission (hCR), with a maintenance remission rate of 59% at 12 months. (N Engl J Med. 2018;378:440)

In 2020, an analysis of registry data from the US Center for International Blood Transplantation (CIBMTR) was reported as treatment results in real clinical practice. (Blood Adv. 2020;4:5414-5424)
Administered to 255 patients with relapsed/refractory B-ALL with a median age of 13.2 (0.4-26.2) years, a median follow-up of 13.4 (3.5-27.9) months, an hCR rate of 85.5%, and a 12-month maintenance remission rate of 60.9 % and ELIANA test yielded similar results.

2. Relapsed or refractory CD19-positive DLBCL

Next, I would like to introduce the results of the global Phase II study (JULIET study) for relapsed/refractory DLBCL. A total of 111 patients with relapsed/refractory B-ALL with a median age of 56 (22-76) years were treated. Median follow-up was 14 (0.1-26) months from administration, objective response rate (ORR) was 52%, including complete remission (CR) in 37 out of 93 evaluable patients (40%), 12-month maintenance response rate was 65%. (N Engl J Med. 2019;380:45)

Similar to B-ALL, the results of treatment in real clinical practice are similar to B-ALL. According to an analysis of the CIBMTR registry data, 155 patients with a median age of 65 (18-88 years) were administered the drug, with a CR rate of 40% and an ORR of 62%. The 12-month progression-free survival rate was 48.4%, slightly inferior to the JULIET trial. It may be that it is being administered to older patients.

3. Adverse events of Kymriah treatment

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are known adverse events specific to Kymriah treatment.
CRS is a systemic inflammatory response triggered by cytokines produced by proliferating and activated CAR-T cells. In clinical trials, the median time from administration to onset was reported to be 3 days, and the median duration was approximately 1 week. In severe cases, ICU management such as artificial ventilation and high-dose vasopressors may be required.
Although the onset mechanism of ICANS is unknown, it is considered a different condition because the median time to onset is 7 days, which is different from that of CRS. Most are transient and recover without treatment.
In preparation for these events, our doctor has established a system that can respond immediately in an emergency by collaborating with ICU doctor and Neurology before administering Kymriah. Long-term susceptibility to infection due to hypogammaglobulinemia requires gammaglobulin replacement.
In addition, although it is not an adverse event, there is also the problem that there are about 10% of cases where manufacturing does not go well.

If you have patients with refractory B-ALL or DLBCL, please introduce them.

Kymriah treatment is a great gospel treatment for relapsed/refractory B-ALL and DLBCL patients. Although there are problems to be overcome, such as the high cost of treatment and insufficient information on long-term treatment results, it is possible to treat other CD19-positive B-cell tumors by changing the target antigen. It is expected that the application will expand to the treatment of refractory hematopoietic tumors and solid cancers. Our hospital intends to contribute to the treatment of refractory B-ALL and DLBCL by taking advantage of its location, where the adjacent Public Interest Incorporated Foundation Kobe Biomedical Innovation Promotion Organization will be Japan's first Kymriah manufacturing and supply facility. If you have a refractory B-ALL patient under the age of 25 or a refractory DLBCL patient with preserved organ function, please do not hesitate to contact us at the stage of inquiry to confirm the indication for Kymriah treatment. I would appreciate it if you could introduce me through the room. Of course, we are looking forward to introducing a wide range of treatments for all blood diseases, including hematopoietic stem cell transplantation.