ISSN 1866-8836
Клеточная терапия и трансплантация

E. Graft-versus-Host Disease

Spirometry findings in bone marrow transplant patients

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Larisa A. Kuzmina, Lidia S. Lubimova, Valeriy G. Savchenko

National Haematologic Scientific Centre, Russian Academy of Medical Sciences Moscow, Russia

Correspondence
Larisa A. Kuzmina, National Haematologic Scientific Centre, Russian Academy of Medical Sciences, Novozykovski pr., 4, 125167, Moscow, Russia, Phone: +7 (916) 148-71-31
E-mail: Kuzlara@rambler.ru

Aim

To investigate the frequency, character of spirometry findings, determine the prognostic of unfavorable alterations, and analyze responses on immunosuppressive therapy (IT) according to the character of spirometry findings in bone marrow transplantation (BMT) recipients.

Methods and materials

The spirometry tests were performed using the national spirometer SMP-21/01–«R-D» with a value of 15 standard tests.  We included 54 recipients of allogeneic BMT: M/F 28/26, aged 17–45, AL – 30, and CML – 24. Myeloablative conditioning (MC) (BU 16 mg/kg+Cph 120 mg/kg) was used. Before BMT spirometry tests were performed in 28 pts during the first year, then 31, and later 32 pts. The total number of investigations was 185. 

Results

The pulmonary functional alterations seen in BMT pts were as follows: restrictive, obstructive, and combined. After BMT the following alterations were revealed in 20 pts (32%): restrictive in 7, obstructive in 6, and bots (combined) in 7. During the first year restrictive alterations (50%) predominated. After 12 mo we generally observed obstructive and combined alterations (80%) in 70% of cases in pts with chronic graft versus host disease (GVHD). There were no adequate correlations between the spirometry results before BMT and the early period after BMT and the later development of  severe lung complications. In those patients that presented restrictive alterations, significant clinical symptoms of pulmonary insufficiency in the majority of pts was not observed: IT was successful. In those patients that presented obstructive alterations, we only observed the improvement or the stabilization of the process in a minority of pts by using a combined long IT. In 6 of the 8 pts with the most severe clinical symptoms – i.e., apnea and oxygen dependence – there were combinate alterations; IT was unsuccessful.

Conclusion

Spirometry is an important method for the definition of the IT strategy in accordance with recognized alterations, especially after 6 mo when GVHD prophylaxis is over. Regular examinations are of great importance, especially in patients with chronic GVHD.

Keywords

spirometry, bone marrow transplantation, BMT, pulmonary complications/ mortality, myeloablative conditioning, MC, graft-versus-host disease, GVHD, immunosuppressive therapy, IT

E. Graft-versus-Host Disease

Evidence of the “graft-versus-tumor” effect following haploidentical transplantation in a patient with a metastatic relapse of Ewing’s sarcoma

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Igor S. Dolgopolov, Roman I. Pimenov, Vasilii K. Boyarshinov, Natalia S. Subbotina, George L. Mentkevich

Institute of Pediatric Oncology and Hematology, Bone Marrow Transplantation Department, Moscow, Russia

A 16-year-old girl was admitted with a metastatic lung relapse of Ewing’s sarcoma six months after completion of multimodal therapy for a localized left shoulder tumor. She received second line ICE chemotherapy with no decrease in tumor volume. She had surgery and 2 and 3 metastases were removed from the right and left lung respectively. No histological response was seen. The appearance of 2 new foci in the right lung was observed within the 2 successive weeks. She received reduced-intensity conditioning, including fludarabine 180 mg/m2, busulfan 8 mg/kg and ATG at 40 mg/kg. She also received 10.8 Gy of whole lung irradiation as part of the conditioning. The donor was the patient's 4/6 HLA-mismatched mother.
The girl was grafted on d0 and +1 with 2.2x106 CD34/kg and 6.7x108CD3/kg after 30’ incubation of inoculum with vincristine and methylprednisolone. GvHD prophylaxis consisted of short courses of methotrexate and cyclosporine A. The level of WBC >1.0x109/l was reached on day +12.
The girl required no PLT transfusion. A complete donor chimerism was observed on d+90. In the early post-transplant period grade I skin GvHD was observed. A cyclosporine-A related encephalopathy occurred on d+60 and the GvHD consisted of MMF and methylprednisolone at that time.
The recovery of immunity was prompt and fast. The decrease in the size of metastases was observed to occur progressively from d+30 until their complete disappearance by day +90. At this time the girl is disease-free and well, with no evidence of GvHD.

As far as we know this is the first report of a successful family-mismatched transplantation with evidence of “graft-versus-tumor” effect in a patient with relapsed Ewing’s sarcoma refractory to second-line therapy.

Keywords

graft-versus-tumor effect, Ewing’s sarcoma, haploidentical transplantation, reduced-intensity conditioning

E. Graft-versus-Host Disease

Chronic graft-versus-host disease in children and adolescents

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Anita Lawitschka

St. Anna Children’s Hospital, Vienna, Austria

Chronic graft-versus-host disease (cGVHD) remains the major late complication of hematopoietic stem cell transplantation (HSCT) and is the main cause of non–relapse mortality (NRM) and morbidity in the long-term follow up. Reported pediatric incidence rates range from 23%–40%, with rising numbers as a result of the increasing use of peripheral blood stem cells, mismatched donors, and adoptive cellular therapies. Compared to adults, considerable fewer studies have been performed in children due to the lower number of patients and because reported data are very heterogeneous. Both cGVHD and therapy may have a profound deleterious impact on organ functions and organ development, hormone balance, and psychomotoric development of the growing child.

Here, we summarize pediatric aspects of risk factors, clinical presentation, and treatment options including supportive and topical therapy. The recently recommended standards for diagnosis and staging are also briefly described. The early identification of high-risk patients, perception of multisystem comorbidities, and exact response evaluation may lead to individualized management of cGVHD patients.

Keywords

pediatric chronic GVHD, diagnosis, staging, treatment, comorbidities, response evaluation

E. Graft-versus-Host Disease

Eye graft-versus-host disease in patients with allogeneic hematopoietic stem cell transplantation (updated data)

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Alexandra L. Mikhaylova1, Yuri S. Astakhov2, Boris V. Afanasyev1

1Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia; 2Chair of Ophthalmology of St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

Graft versus-host-disease (GVHD) is a complication caused by allogeneic hematopoietic stem cell transplantation (HSCT). It can cause dry eye syndrome.

Objectives

To evaluate the probability of eye acute and chronic GVHD (aGVHD and cGVHD) occurrence and response to topical therapy, including drops with cyclosporine 0.05%.

Methods

Two hundred and twelve patients with different hematological malignancies were treated with allogenic HSCT and underwent ophthalmological examination (2006–2009). Dry eye disease stages were diagnosed according to clinical symptoms, positive staining with fluorescein, Schirmer’s I test results, and a tear film break-up time. The treatment schedules were: Stage 1: artificial tears b.i.d. or t.i.d.; Stage 2: artificial tears t.i.d. and dexamethasone 0.1% t.i.d. topical; Stage 3: artificial tears 4–6 times/day, dexamethasone 0.1% t.i.d. topical and cyclosporin A 0.05% 1 drop/eye b.i.d. The Wilcoxon pair matched test, Spearman test, and Pearson test were used for statistical analysis.

Results

Ophthalmologic complications were observed in 48.5% (103/212) of HSCT patients. Eye GVHD was revealed in 25% of patients. Forty-four patients were eligible for assessment of system cGVHD. Among them, 70% (31/44) of patients had signs of dry eye syndrome. All patients with aGVHD received systemic GVHD prophylaxis and eye component of aGVHD responded quickly to local dexamethasone 0.1% treatment. The median day of onset of eye cGVHD was D+145±29. The Table 1 represents eye cGVHD treatment results.

There was a strong correlation between both tests (p=0.004). Three patients could not tolerate cyclosporine topical treatment due to intensive local conjunctive irritation.

Conclusion

About half of treated patients had signs of different eye complications. The frequency of eye cGVHD was 70%. Cyclosporine local therapy proved to be an effective treatment of Stage 3 dry eye syndrome caused by cGVHD.

Keywords

graft-versus-host disease, GVHD, dry eye syndrome, cyclosporin, hematopoietic stem cell transplantation, HSCT

E. Graft-versus-Host Disease

Applying mesenchymal stem cells for the prevention and treatment of steroid-resistant GVHD in children in Belarus

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Nina V. Minakovskaya, Yanina I. Isaikina, Olga V. Aleinikova

Belarusian Research Center for Pediatric Oncology and Hematology, Minsk, Belarus

Correspondence
Nina V. Minakovskaya, Belarusian Research Center for Pediatric Oncology and Hematology, Minski distr., Pos. Lesnoe, Minsk, Belarus, 223053, Phone: +375 17 265 40 89, Fax: +375-17-265-42-22
E-mail: minakovskaya@tut.by

Objective

We analyzed the clinical effect of MSC infusion on day +30 after
HSCT as a GVHD prophylaxis and the application of MSCs as a treatment of severe steroid–resistant GVHD.

Patients and methods

Nine pts after allogeneic hematopoietic stem cell transplantation (HSCT) underwent MSC infusions (median age was 11 years, 6 males, 3 females) between 2006 and 2009.

Diagnoses

ALL – 4, AML – 1, AA – 3, MDS – 1. GVHD prophylaxis for pts with ALL and MDS consisted of CSA and MTX 10 mg/m2 (n=3); for pts with AA, CSA+MMF; for pts with AML, CSA and MTX 10 mg/m2 (n=4). For the treatment of GVHD all pts received methylprednisolone 1–2 mg/kg. Five pts received MSCs once and 4 pts, twice. For 4 pts MSCs were used as a GVHD prophylaxis on day +30 after HSCT; the median dose was 1.0 (0.7–1.5)x10^6/kg. Five pts received MSCs for the treatment of steroid–resistant GVHD with a medium time of MSC infusion after HSCT of 126 (110–151) days and a mean dose of 2.2 (1.3–3.7)x10^6/kg.

Results

There was no evidence of early or late side effects of MSC infusion. One patient died from pulmonary GVHD 1 month after MSC infusion, while eight pts are alive. All pts (n=4) who received MSCs on day +30 as a GVHD prophylaxis developed grades II–IV GVHD and needed a secondary MSC infusion; the median time between MSC infusions was 120(90–150) days.

Four pts out of five with steroid-resistant GVHD showed significant improvement of the clinical signs of GVHD; this allowed the reduction of immunosuppressive therapy and the cessation of steroids.

Conclusion

Our experience demonstrates the absence of a positive GVHD prophylactic efficacy when MSC infusion was carried out on day +30. However, we observed a decrease of GVHD grades III–IV to 0–II, when MSCs were used as a treatment of steroid-resistant GVHD.

Keywords

GVHD, MSC, allogeneic HSCT

E. Graft-versus-Host Disease

The comparative characteristic toxicity and immunosuppressive activity both tacrolimus and cyclosporine in patients undergoing allo-HSCT

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Yulia A. Stankevich, Ludmila S. Zubarovskaya, Elena V. Semenova, Sergey M. Alexeev, Elena V. Babenko, Boris V. Afanasyev

Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

Correspondence
Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: juliastan@spam is badmail.ru

Background

Graft-versus-host disease (GVHD) still remains one the major obstacles to successful allogeneic hematopoietic cell transplantation (HSCT). GVHD is a major cause of morbidity and mortality even when the recipient and donor are matched at the major histocompatibility complex. In its acute and chronic forms, GVHD has an important impact on survival and the recipient’s quality of life. The ability to prevent GVHD – i.e., the application of successful prophylaxis – is the cornerstone of success. Immunosupression with pharmacological agents such as cyclosporine (CsA) or tacrolimus (Tx) is more often used for GVHD prophylaxis. Because they share a common intracellular target, the toxicity profiles of CsA and Tx are very similar. We found Tx to be superior for the prophylaxis of acute GVHD, but more toxic. While hypertension and myelosupression is more commonly seen with CsA, neurological, nephrology, and gastrointestinal side effects are more often associated with the administration of Tx.

Patients and methods

From 2000 to December 2008, 171 patients (pts) received allogeneic HSCT. In two patients allo-HSCT was repeated because of relapse of disease, so the total number of transplantations was 173. Patients and donor characteristics, type of allo-HSCT, and preparing regimens are shown in Table 1.

Results

There was no significant difference in survival. The 6-month overall survival rate was 53% for the Tx group and 65% for the CsA group; the 6-month relapse-free survival rate was 42% (Tx) vs. 50% (CsA). There was no difference in rates of relapse between the two groups.

Infections were the most common cause of death, accounting for 33% of deaths. Other causes of death included acute GVHD (31%), relapse (20%), and multisystem organ failure (8%). The incidence of infections was similar in the two study groups.

Although a significantly greater proportion of patients was treated with cyclosporine, the incidence of grades II-IV acute GVHD was significantly lower in patients who received tacrolimus (29% vs. 54% in related HSCT and 32% vs. 60% in unrelated HSCT).

Despite the fact that Tx proved to be superior as a prophylaxis of acute GVHD, it was found to be more toxic. The incidence of hypertension was significantly higher in the CsA group (38% vs. 24%), but neurological complications (headache, tremor, paresthesia) were significantly higher in the Tx group (44% vs. 30%). Gastrointestinal disturbances were more common in the Tx group (46% vs. 36%, NS), as was hyperglycemia (24% vs. 16%), nephrotoxicity (19% vs. 15%), and metabolic disturbances (11% vs. 7%).

Conclusion

The use of Tx seems to be preferable in groups with a higher risk of developing GVHD because it has a more potent immunosuppressive effect. But Tx has more toxic complications such as neurological, nephrology, gastrointestinal, and metabolic disturbances. On the other hand, hypertension and myelosuppression is more commonly seen with CsA.

Keywords

graft-versus-host disease, allogeneic hematopoietic cell transplantation, immunosuppressive therapy