Compassionate Use of the CliniMACS® CD34 Reagent System for Patients Requiring a Post Hematopoietic Stem Cell Transplant Boost of Donor Hematopoietic Stem Cells

Successful engraftment after allogeneic hematopoietic stem cell transplant (HSCT) is defined by an actual neutrophil count (ANC) of > 500 10^6/L and a self-sustaining platelet count of 20 x 10^9/L. ANC recovery usually occurs 14 to 21 days after the infusion of donor HSCs with red cell and platelet recovery typically following within the same time frame, although resolution of anemia may occur last. Recovery time is dose dependent, but in one report, donor HSC aliquots containing 1.9 to 20.5 10^6/kg CD34+ cells resulted in an ANC of > 500 10^6/L at a median of 12 days and 16 days for patients receiving filgrastim versus those not receiving a white cell growth factor. In this trial, self-sustaining platelet counts of 20 x 10^9/L occurred at median times of 15 to 11 days respectively. The results of another trial comparing outcomes between patients receiving mobilized peripheral blood stem cells (PBSCs) versus those receiving marrow from their donors showed that median times ANC of > 500 10^6/L and self-sustaining platelet counts of 20 x 10^9/L were 16 and 13 days respectively in the group receiving PBSCs and 21 and 19 days in those receiving marrow. Similar HSC doses associated with successful engraftment in these time frames have been demonstrated in other trials.

Most transplant centers require a minimum dose of 1 to 2 x 10^6 CD34+ cells/kg to achieve adequate count recovery in a reasonable time frame post HSCT, although an early trial examining recovery after autologous reinfusion of HSCs demonstrated that a threshold of 2.5 x 10^6/kg of CD 34 cells was associated with consistent and rapid WBC and platelet recovery times (18 and 14 days respectively). A later trial assessing autologous PBSC mobilization in breast cancer patients showed that HSC doses of ≥ 5 x 10^6 CD34+ cells/kg were associated with an 85% probability of WBC and platelet recovery by day 14, but with doses of 2 x 10^6 or less, 10% of patients had platelet recovery beyond day +28. While the precise dose of HSCs for successful engraftment in the allogeneic setting is not known, patient characteristics such as myelofibrosis and/or splenomegaly are likely to cause interpatient variation in the minimum number of HSCs needed for successful engraftment. In addition, donor factors such as mismatch in size with the recipient and biologic variation in the number of HSCs that can be obtained from any individual donor, can create a deficit in the amount of HSCs required for robust count recovery in a particular recipient. All of these factors can contribute to a poor functional or numeric cell dose and result in pancytopenia after HSCT.

Drugs required for the prophylaxis and treatment of GVHD and infection have myelotoxic effects post HSCT, and unlike their use in solid organ transplantation, the marrow toxic effects of these drugs are potentially more severe and longer lasting in the presence of a newly reconstituting immune system. While many drugs can have negative effects on marrow function after HSCT, mycophenolate mofetil (MMF) and ganciclovir are two of the most commonly used agents with the potential to cause cytopenias.

After hydrolysis to its active form, mycophenolic acid (MPA), MMF inhibits T and B cell proliferation making its use valuable in the prevention of graft versus host and host versus graft reactions post HSCT, especially in conjunction with a calcineurin inhibitor. Levels of MPA are increased in the presence of altered renal function, and other commonly used post HSCT drugs including acyclovir, ganciclovir, valaganciclovir, and tacrolimus. A major side effect of MMF is pancytopenia, particularly neutropenia, which is exacerbated by high drug levels. Due to finding of a wide interpatient variability in drug exposure, it has recently been recommended that the monitoring of MPA levels would result in better therapeutic outcomes, although MPA drug levels are not commonly obtained as yet in clinical practice. Myelotoxicity from the drug is observed after renal transplantation in the presence of a non-transplanted immune system demonstrating the potent myelosuppression associated with this drug, and the increased toxicity in patients with abnormal renal function. Patients post HSCT are treated with multiple drugs that both increase MPA levels and alter creatinine clearance, and are thereby highly susceptible to the marrow toxic effects of the drug which can result in cytopenias.

Ganciclovir and valganciclovir, which is rapidly converted to ganciclovir by intestinal mucosal cells and hepatocytes to ganciclovir, are inhibitors of DNA synthesis. Ganciclovir is a known myelotoxic drug that is effective in prophylaxis and treatment of cytomegalovirus (CMV) infections in transplant recipients. Salzberger et al. examined the outcomes between engraftment and day +100 post HSCT of 278 patients receiving ganciclovir and found that 41% of patients receiving the drug had an ANC less than 1000 10^6/L for at least 2 consecutive days. Hyperbilirubinemia during the first 20 days after HSCT, elevated serum creatinine after day +21, and low marrow cellularity between days +21 and +28 were significant risk factors for neutropenia. Patients with 3 risk factors had a 57% chance of developing neutropenia, which was significantly associated with a decreased overall and event free survival. As noted above, concomitant use of ganciclovir and MMF increase the serum concentration of both drugs exacerbating marrow toxicity. Because CMV is a life-threatening disease post HSCT, it is often necessary to use ganciclovir especially in the presence of renal failure which is exacerbated with the use of foscarnet, the alternate drug for CMV treatment. Therefore, ganciclovir-induced pancytopenia may be unavoidable in certain contexts.